PermiT: Permissive Underfeeding in Critically Ill Patients (2015)

“In this randomized trial, we found no significant difference in 90-day mortality between critically ill adults who received a moderate amount of calories from enteral nutrition and those who received a full amount of calories.”

  • The PermiT Trial Investigators

1. Publication Details

  • Trial Title: Permissive Underfeeding or Standard Enteral Feeding in Critically Ill Adults
  • Citation: Arabi YM, Aldawood AS, Haddad SH, et al. Permissive Underfeeding or Standard Enteral Feeding in Critically Ill Adults. N Engl J Med. 2015;372(25):2398-2408. DOI: 10.1056/NEJMoa1502826
  • Published: June 18, 2015, in The New England Journal of Medicine
  • Author: Yaseen M. Arabi, M.D.
  • Funding: King Abdullah International Medical Research Center, Saudi Arabia.

2. Keywords

  • Critical Care, Nutrition, Enteral Nutrition, Permissive Underfeeding, Hypocaloric Feeding, Randomized Controlled Trial

3. The Clinical Question

  • In critically ill adults requiring mechanical ventilation (Population), does a strategy of permissive underfeeding (hypocaloric feeding) (Intervention) compared to a strategy of standard, full enteral feeding (Comparison) affect 90-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Providing early enteral nutrition is a standard of care in the ICU. However, the optimal caloric target was a major controversy. While aiming for full caloric replacement seemed logical, observational data and smaller trials suggested that “permissive underfeeding” (intentionally providing fewer calories) might be safe and could potentially avoid complications associated with overfeeding in the acute phase of critical illness.
  • Knowledge Gap: There was no high-quality evidence from a large, multicenter randomized trial to definitively compare a hypocaloric feeding strategy to a standard full-feeding strategy in a general ICU population.
  • Proposed Hypothesis: The authors hypothesized that permissive underfeeding would be non-inferior to standard enteral feeding with respect to 90-day mortality.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, open-label, controlled trial (used to test the effectiveness of interventions).
  • Setting: 7 intensive care units (ICUs) in Saudi Arabia and Canada.
  • Trial Period: Enrollment ran from November 2009 to May 2014.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) who were receiving mechanical ventilation and were expected to require it for more than 48 hours.
    • Exclusion Criteria: Included pregnancy, contraindications to enteral feeding, and severe malnutrition at baseline.
  • Intervention: A permissive underfeeding strategy, where patients received enteral nutrition to provide 40% to 60% of their calculated caloric needs for up to 14 days.
  • Control: A standard feeding strategy, where enteral nutrition was advanced to provide 70% to 100% of calculated caloric needs.
  • Management Common to Both Groups: Both groups received the same amount of protein. All other aspects of ICU care were at the discretion of the treating clinicians.
  • Power and Sample Size: The authors calculated that a sample size of 894 patients would provide 80% power to detect a 7.5% absolute risk reduction in 90-day mortality. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80% is the standard accepted level for clinical trials).
  • Outcomes:
    • Primary Outcome: All-cause mortality at 90 days.
    • Secondary Outcomes: Included 28-day and 180-day mortality, incidence of infections, and duration of organ support.

6. Key Results

  • Enrollment and Baseline: 894 patients were randomized (448 to permissive underfeeding and 446 to standard feeding). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in 90-day mortality. 119 of 448 patients (26.6%) in the permissive-underfeeding group died, compared with 127 of 446 patients (28.5%) in the standard-feeding group (p=0.58).
  • Secondary Outcomes: There were no significant differences between the groups in any of the secondary outcomes, including rates of infection, ventilator-free days, or ICU length of stay.
  • Adverse Events: The incidence of adverse events, including diarrhea and high gastric residual volumes, was similar in both groups.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of death between the two groups.
  • Key Statistic(s) Reported: Relative Risk (RR) for death at 90 days: 0.93 (95% CI, 0.76 to 1.15; P-value: 0.58).
  • Interpretation of Key Statistic(s):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk in Intervention Group) / (Risk in Control Group).
      • Calculation: The paper reports the result as 0.93.
      • Clinical Meaning: An RR of 0.93 suggests a non-significant 7% lower relative risk of death in the permissive-underfeeding group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 0.76 to 1.15.
      • Clinical Meaning: Since this range crosses the line of no effect (1.0), it confirms that the result is not statistically significant. Clinically, this means the true effect could range from a 24% benefit to a 15% harm.
    • P-value: The p-value of 0.58 is much higher than the 0.05 threshold, indicating the result is not statistically significant and very likely due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures: As the trial was neutral, ARR and NNT are not applicable.
  • Subgroup Analyses: No significant differences were found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The large, multicenter, randomized, controlled design provided high-quality evidence on an important clinical question.
  • Generalizability: The pragmatic design and inclusion of a broad population of critically ill patients make the findings highly generalizable to real-world practice.
  • Statistical Power: The study was large and adequately powered to confidently rule out a modest but clinically important mortality difference.
  • Patient-Centered Outcomes: The primary outcome of 90-day mortality is a robust and patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label (unblinded), which introduces a risk of performance bias.
  • External Validity (Generalizability): The study population was generally well-nourished at baseline and specifically excluded patients with severe malnutrition. The findings may not be applicable to this high-risk group.
  • Other: A key strength and unique feature of the trial was that both groups received the same amount of protein, isolating the effect of caloric intake.

10. Conclusion of the Authors

  • The authors concluded that in critically ill adults, permissive underfeeding was not associated with a different 90-day mortality rate than standard enteral feeding.

11. To Summarize

  • Impact on Current Practice: This was a landmark trial that provided strong evidence that a strategy of intentional underfeeding (while maintaining protein intake) is safe and not inferior to a strategy of aiming for full caloric replacement in the first two weeks of critical illness.
  • Specific Recommendations:
    • Patient Selection: For the broad population of adult ICU patients requiring mechanical ventilation who are not severely malnourished at baseline.
    • Actionable Intervention: A strategy of permissive underfeeding (targeting 40-60% of caloric needs) is a safe and acceptable alternative to attempting full feeding.
  • What This Trial Does NOT Mean: This trial does NOT mean that nutrition is unimportant or that patients should be starved. It specifically tested a hypocaloric, isonitrogenous strategy.
  • Implementation Caveats: The key takeaway is that avoiding overfeeding in the acute phase of critical illness is important. A strategy of permissive underfeeding simplifies nutrition delivery and may be associated with fewer interruptions.

12. Context and Related Studies

  • Building on Previous Evidence: The PermiT trial (2015) was designed to provide a definitive answer to the “how much to feed” question, building on the findings of earlier trials like EDEN (2012) and EPaNIC (2011) which also supported a more conservative approach to early nutrition.
  • Influence on Subsequent Research: The definitive neutral finding of this trial has been highly influential in shaping modern ICU nutrition guidelines, which now broadly support a more conservative, permissive underfeeding approach in the first week of critical illness for most patients.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The optimal nutritional strategy for patients with pre-existing severe malnutrition remains an important unanswered question. The ideal protein dose in critical illness is also an area of active investigation.
  • Future Directions: Future research is focused on identifying which specific subgroups of patients (e.g., those with different inflammatory or metabolic profiles) might benefit from earlier or more aggressive nutritional support.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a very common and fundamental aspect of ICU care.
  • Methods: The large, multicenter, randomized controlled trial design was appropriate and robust. The main methodological weakness is the open-label design. A key strength was the isonitrogenous design, which isolated the effect of calories.
  • Results: The study reported a clear neutral finding for its primary outcome and all major secondary outcomes. This provides strong evidence against a meaningful clinical benefit of early full caloric feeding in this population.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data. The high external validity of this pragmatic trial means its findings are broadly applicable. This is a classic example of a high-quality “negative” trial that was profoundly practice-changing by providing strong evidence that a less aggressive and simpler strategy is not inferior to a more complex one.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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